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Loss of testosterone impairs anti-tumor neutrophil function
In men, the incidence of melanoma rises rapidly after age 50, and nearly two thirds of melanoma deaths are male. The immune system is known to play a key role in controlling the growth and spread of malignancies, but whether age- and sex-dependent changes in immune cell function account for this effect remains unknown. Here, we show that in castrated male mice, neutrophil maturation and function are impaired, leading to elevated metastatic burden in two models of melanoma. Replacement of testosterone effectively normalized the tumor burden in castrated male mice. Further, the aberrant neutrophil phenotype was also observed in prostate cancer patients receiving androgen deprivation therapy, highlighting the evolutionary conservation and clinical relevance of the phenotype. Taken together, these results provide a better understanding of the role of androgen signaling in neutrophil function and the impact of this biology on immune control of malignancies.
It is known that there are sex differences in the incidence and prognosis of certain cancers, including melanoma. In this study, the authors utilize a melanoma model to reveal that castrated mice have a higher metastatic burden associated with androgen dependent impaired neutrophil function.
Journal Article
Rapid effects of valproic acid on the fetal brain transcriptome: implications for brain development and autism
There is an increased incidence of autism among the children of women who take the anti-epileptic, mood-stabilizing drug, valproic acid (VPA) during pregnancy; moreover, exposure to VPA in utero causes autistic-like symptoms in rodents and non-human primates. Analysis of RNA-seq data obtained from E12.5 fetal mouse brains 3 hours after VPA administration to the pregnant dam revealed that VPA rapidly and significantly increased or decreased the expression of approximately 7,300 genes. No significant sex differences in VPA-induced gene expression were observed. Expression of 399 autism risk genes was significantly altered by VPA as was expression of 258 genes that have been reported to modulate fetal brain development but are not otherwise linked to autism. Expression of genes associated with intracellular signaling pathways, neurogenesis, and excitation-inhibition balance as well as synaptogenesis, neuronal fate determination, axon and dendritic development, neuroinflammation, circadian rhythms, and epigenetic modulation of gene expression was dysregulated by VPA. Notably, at least 40 genes that are known to regulate embryonic neurogenesis were dysregulated by VPA. The goal of this study was to identify mouse genes that are: (a) significantly up- or downregulated by VPA in the fetal brain and (b) associated with autism and/or known to play a role in embryonic neurodevelopmental processes, perturbation of which has the potential to alter brain connectivity and, consequently behavior, in the adult. The genes meeting these criteria provide potential targets for future hypothesis-driven studies to elucidate the proximal causes of errors in brain connectivity underlying neurodevelopmental disorders such as autism.
Journal Article
Itaconate ameliorates cardiovascular inflammation in a mouse model of Kawasaki disease vasculitis – brief report
Kawasaki disease (KD), a systemic vasculitis and the leading cause of acquired heart disease in children, stems from an uncontrolled inflammatory response that fails to resolve in up to 20% of IVIG-treated patients. This treatment resistance increases the risk of cardiovascular complications and highlights the need for more targeted therapeutics.
We used the
cell wall extract (LCWE) murine model of KD vasculitis to investigate the therapeutic potential of itaconate, an anti-inflammatory metabolite, in the pathogenesis of KD. The expression of aconitate decarboxylase 1 (
), which encodes the mitochondrial enzyme that produces itaconate, was assessed in both samples from KD patients and vascular tissues of LCWE-injected mice. LCWE-injected mice were treated with itaconate, and the severity of LCWE-induced KD vasculitis was evaluated.
LCWE injection led to the development of cardiovascular lesions, specifically aortitis, coronary arteritis, and abdominal aorta dilatation. Expression of
was upregulated in KD patients during the acute phase of the disease and in cardiovascular lesions of LCWE-injected mice. Treatment with itaconate significantly reduced the development of LCWE-induced cardiovascular lesions. Mechanistically, exogenous itaconate suppressed NLRP3 inflammasome activation in LCWE-induced cardiovascular lesions and decreased IL-1β secretion.
Itaconate treatment provides cardiovascular protection in an experimental mouse model of KD vasculitis by decreasing NLRP3 inflammasome activation and reducing vascular inflammation. Itaconate may be a promising therapeutic agent for patients with KD.
Journal Article
Platelets exacerbate cardiovascular inflammation in a murine model of Kawasaki disease vasculitis
Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Increased platelet counts and activation are observed during the course of KD, and elevated platelet counts are associated with higher risks of developing intravenous immunoglobulin resistance and coronary artery aneurysms. However, the role of platelets in KD pathogenesis remains unclear. Here, we analyzed transcriptomics data generated from the whole blood of patients with KD and discovered changes in the expression of platelet-related genes during acute KD. In the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis, LCWE injection increased platelet counts and the formation of monocyte-platelet aggregates (MPAs), upregulated the concentration of soluble P-selectin, and increased circulating thrombopoietin and interleukin 6 (IL-6). Furthermore, platelet counts correlated with the severity of cardiovascular inflammation. Genetic depletion of platelets (Mpl-/- mice) or treatment with an anti-CD42b antibody significantly reduced LCWE-induced cardiovascular lesions. Furthermore, in the mouse model, platelets promoted vascular inflammation via the formation of MPAs, which likely amplified IL-1B production. Altogether, our results indicate that platelet activation exacerbates the development of cardiovascular lesions in a murine model of KD vasculitis. These findings enhance our understanding of KD vasculitis pathogenesis and highlight MPAs, which are known to enhance IL-1B production, as a potential therapeutic target for this disorder.
Journal Article
Basic Science and Pathogenesis
Alzheimer's disease (AD) is a progressive irreversible dementia characterized by beta-amyloid protein plaque deposition and hyperphosphorylation of tau forming neurofibrillary tangles, and neurodegeneration. An emerging theory posits that infections could be one of the triggering factors in AD development and progression. Multiple lines of evidence have linked Chlamydia pneumoniae (Cp), a gram-negative obligate intracellular bacterium with AD. Cp has been detected in the post-mortem brain tissues of AD patients, however, pathomechanisms associated with Cp in AD remain unknown.
Transgenic APP
/PS1
(ADtg) mice and non-tg wildtype (WT) littermates were infected with Cp intranasally and sacrificed either 1 week or 6 months after infection. Mice were perfused with saline, and the brains were harvested for subsequent analysis, including PCR, flow cytometry, immunofluorescence, and live Cp growth. Neurobehavioral functions were assessed through an open field, visual-stimuli X maze, and Barnes maze tests. Primary microglia and astrocytes were infected with Cp and cytokine and chemokines production was measured by ELISA.
We found Cp in the olfactory bulb and brain of mice 7 days after infection and the infiltration of inflammatory cells into the brain. Cp infection resulted in microglial activation. Immunohistochemical analysis also revealed the activation of microglia and astrocytes in the Cp-infected mouse brain. In addition, Cp infection led to increased mRNA expression of neuroinflammatory mediators such as cytokines and chemokines. Primary astrocytes and microglia cultures could sustain Cp growth and produce proinflammatory cytokines and chemokines in response to infection. Live Cp in the brain was also observed 7 months after infection and the Cp load was higher in ADtg mice than WT. Cp infection resulted in significant cognitive decline in both WT as well as ADtg mice together with increased AD-related neuropathology.
Intranasal Cp infection leads to brain colonization and altered Iba1 immunoreactivity. Both primary astrocytes and microglia support Cp growth and produce neuroinflammatory cytokines. Long-term Cp infection promotes neuroinflammation and cognitive decline in mice along with increased Aβ deposits. Cognitive impairment in Cp-infected ADtg and WT mice as well as increased Aβ in ADtg mice suggest that Cp infection may play an important pathological role in AD development.
Journal Article
Oxidative DNA Damage Accelerates Skin Inflammation in Pristane-Induced Lupus Model
Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2'-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE.
mice showed increased influx of Ly6C
monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of
was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of
mice had significantly higher expression of type I IFN genes (
, and
). In keeping with loss of
resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent
expression was observed in BMDMs from
mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates
expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced
expression in monocytes associated with skin involvement in SLE patients and the expression of
was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.
Journal Article
Long-term cardiovascular inflammation and fibrosis in a murine model of vasculitis induced by Lactobacillus casei cell wall extract
Kawasaki disease (KD), an acute febrile illness and systemic vasculitis, is the leading cause of acquired heart disease in children in industrialized countries. KD leads to the development of coronary artery aneurysms (CAA) in affected children, which may persist for months and even years after the acute phase of the disease. There is an unmet need to characterize the immune and pathological mechanisms of the long-term complications of KD.
We examined cardiovascular complications in the
cell wall extract (LCWE) mouse model of KD-like vasculitis over 4 months. The long-term immune, pathological, and functional changes occurring in cardiovascular lesions were characterized by histological examination, flow cytometric analysis, immunofluorescent staining of cardiovascular tissues, and transthoracic echocardiogram.
CAA and abdominal aorta dilations were detected up to 16 weeks following LCWE injection and initiation of acute vasculitis. We observed alterations in the composition of circulating immune cell profiles, such as increased monocyte frequencies in the acute phase of the disease and higher counts of neutrophils. We determined a positive correlation between circulating neutrophil and inflammatory monocyte counts and the severity of cardiovascular lesions early after LCWE injection. LCWE-induced KD-like vasculitis was associated with myocarditis and myocardial dysfunction, characterized by diminished ejection fraction and left ventricular remodeling, which worsened over time. We observed extensive fibrosis within the inflamed cardiac tissue early in the disease and myocardial fibrosis in later stages.
Our findings indicate that increased circulating neutrophil counts in the acute phase are a reliable predictor of cardiovascular inflammation severity in LCWE-injected mice. Furthermore, long-term cardiac complications stemming from inflammatory cell infiltrations in the aortic root and coronary arteries, myocardial dysfunction, and myocardial fibrosis persist over long periods and are still detected up to 16 weeks after LCWE injection.
Journal Article
Autophagy-mitophagy induction attenuates cardiovascular inflammation in a murine model of Kawasaki disease vasculitis
Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Murine and human data suggest that the NLRP3-IL-1β pathway is the main driver of KD pathophysiology. NLRP3 can be activated during defective autophagy/mitophagy. We used the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to examine the role of autophagy/mitophagy on cardiovascular lesion development. LCWE-injected mice had impaired autophagy/mitophagy and increased levels of ROS in cardiovascular lesions, together with increased systemic 8-OHdG release. Enhanced autophagic flux significantly reduced cardiovascular lesions in LCWE-injected mice, whereas autophagy blockade increased inflammation. Vascular smooth muscle cell-specific deletion of Atg16l1 and global Parkin-/- significantly increased disease formation, supporting the importance of autophagy/mitophagy in this model. Ogg1-/- mice had significantly increased lesions with increased NLRP3 activity, whereas treatment with MitoQ reduced vascular tissue inflammation, ROS production, and systemic 8-OHdG release. Treatment with MN58b or Metformin (increasing AMPK and reducing ROS) resulted in decreased cardiovascular lesions. Our results demonstrate that impaired autophagy/mitophagy and ROS-dependent damage exacerbate the development of murine KD vasculitis. This pathway can be efficiently targeted to reduce disease severity. These findings enhance our understanding of KD pathogenesis and identify potentially novel therapeutic avenues for KD treatment.
Journal Article
Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model
Hot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17β-estradiol, E2) are produced from testosterone. Although estrogens alleviate hot flushes in these patients, they also cause adverse systemic side effects. Because only estrogens can provide mitigation of hot flushes on the basis of current clinical practices, there is an unmet need for an effective and safe pharmacotherapeutic intervention that would also greatly enhance patient adherence. To this end, we evaluated treatment of orchidectomized (ORDX) rats with 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective bioprecursor prodrug of E2. A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E2 in the brain without the appearance of the hormone in the circulation. Therefore, DHED treatment alleviated androgen deprivation-associated hot flushes without peripheral impact in the ORDX rat model. Concomitantly, we showed that DHED-derived E2 induced progesterone receptor gene expression in the hypothalamus without stimulating galanin expression in the anterior pituitary, further indicating the lack of systemic estrogen exposure upon oral treatment with DHED.
Journal Article